Lindberg U H, Thorberg S O, Bengtsson S, Renyi A L, Ross S B, Ogren S O
J Med Chem. 1978 May;21(5):448-56. doi: 10.1021/jm00203a008.
A series of alpha-amino acid esters of substituted phenethyl alcohols was prepared and tested as inhibitors of the neuronal reuptake of noradrenaline and 5-hydroxytryptamine. Some of the compounds are potent and very selective in blocking the 5-hydroxytryptamine uptake, as evidenced by biochemical data and behavioral tests. The most promising agent, alaproclate [2-(4-chlorophenyl)-1,1-dimethylethyl 2-aminopropanoate hydrochloride (I, IV)], was selected for further studies as a potential antidepressant agent. A discussion on structure--activity relationships (SAR) is given. In an attempt to explain the selective action on the mechanism of 5-hydroxytryptamine uptake by the new inhibitors, their structures are compared with those of the two neurotransmitters. From the tentative pharmacophore and conformations of transmitter (5-HT) and inhibitor (alaproclate) derived from SAR, a hypothetic carrier site for 5-HT uptake is deduced in terms of geometry and electronic properties.
制备了一系列取代苯乙醇的α-氨基酸酯，并将其作为去甲肾上腺素和5-羟色胺神经元再摄取抑制剂进行测试。生化数据和行为测试表明，其中一些化合物在阻断5-羟色胺摄取方面具有强效且高度选择性。最有前景的药物阿拉丙酯[2-(4-氯苯基)-1,1-二甲基乙基2-氨基丙酸盐酸盐(I,IV)]被选为潜在的抗抑郁药进行进一步研究。文中给出了结构-活性关系(SAR)的讨论。为了解释新抑制剂对5-羟色胺摄取机制的选择性作用，将它们的结构与两种神经递质的结构进行了比较。从SAR推导的递质(5-HT)和抑制剂(阿拉丙酯)的暂定药效团和构象出发，根据几何和电子性质推导出5-HT摄取的假设载体位点。
